Effect of aspirin, warfarin, and proton-pump inhibitors on performance of fecal immunochemical test in colorectal cancer screening: a systematic review and meta-analysis.

This study aims to investigate the impact of antithrombotic agents and proton-pump inhibitors (PPIs) on fecal immunochemical test (FIT). PubMed, EMBASE, Web of Science, Cochrane Central, and Google Scholar were searched from inception until September 3, 2023. Studies comparing the diagnostic performance of FIT between medicine users and non-users in average-risk colorectal cancer screening populations were included. Pooled sensitivity, specificity, and positive predictive values (PPVs) for advanced neoplasia (AN) of FIT were compared by reporting pooled odds ratios (ORs) with 95% confidence intervals (CIs) using a random-effects model. Twenty-two studies enrolling 5,572,367 individuals were included. For aspirin, pooled sensitivity and specificity for AN were 57.2% and 88.4% in users versus 60.2% and 93.2% in non-users; while pooled ORs were 1.49 (95% CI 0.89-2.48, P = 0.13) and 0.72 (95% CI 0.62-0.83, P < 0.001), respectively. In subgroup analysis, there was no difference in sensitivity and specificity between the two groups at the cutoff of 20 µg Hb/g (P = 0.57 and 0.29, respectively) but a significantly lower specificity in users compared with non-users at lower cutoffs (P < 0.001). Moreover, a significantly lower PPVAN in users compared with non-users was observed after matching age and sex confounders (P = 0.001). Warfarin had no significant influence on PPVAN of FIT (P = 0.43). PPIs were associated with a significantly lower PPVAN in users (P < 0.001). Aspirin use was associated with lower specificity and PPV of FIT. Aspirin discontinuation before FIT to reduce false-positive results should be interpreted with caution given concerns about cardiovascular events. Increasing cutoff values of FIT in aspirin users may be another possible approach. Additionally, warfarin withdrawal before FIT is unnecessary but PPIs withdrawal before FIT is recommended to reduce false-positive results.

PVA enema ameliorates DSS-induced acute colitis in mice.

BACKGROUND: Ulcerative colitis (UC) represents a clinically challenging condition characterized by persistent damage to the colonic epithelial mucosa as the principal pathological feature. Polyvinyl alcohol (PVA) solution, primarily composed of glue, is a biodegradable polymer material that has found utility in the medical field. This research endeavors to investigate the therapeutic potential of PVA water solution in ameliorating UC in mice. METHODS: UC was induced in 48 C57BL/6 mice by administering 2.5% DSS in their diet for 6 days. Mice were treated with different concentrations of PVA (0.1 mg/ml PVA, 0.3 mg/ml PVA, 1 mg/ml PVA, 3 mg/ml PVA, 10 mg/ml PVA) enemas (n = 6). Disease Activity Index (DAI) and histologic score were evaluated for inflammation degree. Furthermore, mouse colon organoids were cultured, which were used to assess the effects of PVA on expansion in vitro. RESULTS: PVA aqueous solutions (1 mg/ml and 3 mg/ml) were able to alleviate the DAI in mice. By DAY 6, there was a significant 3/5-fold decrease in DAI within the 1 mg/ml PVA group (p = 0.02). Histopathology scores demonstrated improvements, while the levels of inflammatory factors in the intestinal mucosal tissue were reduced. Additionally, it was confirmed that PVA could promote the expansion of colonic organoids in vitro. CONCLUSIONS: In summary, our investigation has yielded findings indicating that PVA holds the potential to ameliorate symptoms associated with colitis in murine subjects afflicted by DSS-induced colitis, primarily through its facilitation of intestinal stem cell expansion. This study might provide a new candidate for the clinical treatment of ulcerative colitis.

Bile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides.

Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease.

Digital Spatial Profiling Reveals Functional Shift of Enterochromaffin Cell in Patients With Ulcerative Colitis.

As a major component of the enteroendocrine system, enterochromaffin (EC) cells play a key role in ulcerative colitis (UC). However, the scarcity of EC cells has limited the investigation of their function. In this study, we applied digital spatial profiling to acquire transcriptomic data for EC cells and other epithelial cells from colonoscopic biopsy samples from eight patients with UC and seven healthy controls. Differential expression analysis, gene set enrichment analysis, and weighted gene coexpression network analysis were performed to identify differentially expressed genes and pathways and coexpression networks. Results were validated using an online dataset obtained by single-cell RNA sequencing, along with immunofluorescence staining and quantitative real-time PCR. In healthy participants, 10 genes were significantly enriched in EC cells, functionally concentrated in protein and bioamine synthesis. A coexpression network containing 17 hub genes, including TPH1, CHGA, and GCLC, was identified in EC cells. In patients with UC, EC cells gained increased capacity for protein synthesis, along with novel immunological functions such as antigen processing and presentation, whereas chemical sensation was downregulated. The specific expression of CHGB and RGS2 in EC cells was confirmed by immunofluorescence staining. Our results illuminate the transcriptional signatures of EC cells in the human colon. EC cells' newly observed functional shift from sensation to secretion and immunity indicates their pivotal role in UC.

Involvement of mucosal flora and enterochromaffin cells of the caecum and descending colon in diarrhoea-predominant irritable bowel syndrome.

BACKGROUND: Accumulating evidence supports the pivotal role of intestinal flora in irritable bowel syndrome (IBS). Serotonin synthesis by enterochromaffin (EC) cells is influenced by the gut microbiota and has been reported to have an interaction with IBS. The comparison between the microbiota of the caecal and colonic mucosa in IBS has rarely been studied. The aim of this study was to investigate the relationship between the gut microbiota, EC cells in caecum and descending colon, and diarrhoea-predominant IBS (IBS-D) symptoms. RESULTS: A total of 22 IBS-D patients and 22 healthy controls (HCs) were enrolled in our study. Hamilton anxiety (HAM-A) and Hamilton depression (HAM-D) grades increased significantly in IBS-D patients. In addition, the frequency of defecation in IBS-D patients was higher than that in HCs. Among the preponderant bacterial genera, the relative abundance of the Ruminococcus_torques_ group increased in IBS-D patients in caecum samples while Raoultella and Fusobacterium were less abundant. In the descending colon, the abundance of the Ruminococcus_torques_group and Dorea increased in IBS-D patients and Fusobacterium decreased. No difference was observed between the descending colon and caecum in regards to the mucosal-associated microbiota. The number of EC cells in the caecum of IBS-D patients was higher than in HCs and the expression of TPH1 was higher in IBS-D patients both in the caecum and in the descending colon both at the mRNA and protein level. Correlation analysis showed that the Ruminococcus_torques_group was positively associated with HAM-A, HAM-D, EC cell number, IBS-SSS, degree of abdominal pain, frequency of abdominal pain and frequency of defecation. The abundance of Dorea was positively associated with EC cell number, IBS-SSS, HAM-A, HAM-D and frequency of abdominal pain. CONCLUSIONS: EC cell numbers increased in IBS-D patients and the expression of TPH1 was higher than in HCs. The Ruminococcus torques group and Dorea furthermore seem like promising targets for future research into the treatment of IBS-D patients.

Quality Improvement of Sample Collection Increases the Diagnostic Accuracy of Quantitative Fecal Immunochemical Test in Colorectal Cancer Screening: A Pilot Study.

Objective: The diagnostic efficiency of the quantitative fecal immunochemical test (qFIT) has large variations in colorectal cancer (CRC) screening. We aimed to explore whether the practical sample collection operant training could improve the diagnostic accuracy of the qFIT in CRC screening. Methods: Moderate-/high-risk individuals aged 50-75 years old were invited to participate in a prospective observational study between July 2020 and March 2021. Participants took a qFIT sample without fecal sample collection operant training in advance and then completed another qFIT sample after the operant training. The primary outcome was the sensitivity and specificity of the qFITs for CRC and advanced colorectal neoplasia (ACRN). The secondary outcome was the difference in the area under the curves (AUCs) and the concentrations of the fecal hemoglobin (Hb) between the qFIT without and after the operant training. Results: Out of 913 patients, 81 (8.9%) patients had ACRN, including 25 (2.7%) patients with CRC. For CRC, the sensitivities of the qFIT without and after the operant training at 10 µg/g were 80.4 and 100.0%, respectively, and the specificities were 90.1 and 88.4%, respectively. For ACRN, the sensitivities were 49.4 and 69.1% and the specificities were 91.7 and 91.3%, respectively. The AUC of the qFIT after the operant training was significantly higher than that without the operant training for CRC (p = 0.027) and ACRN (p = 0.001). After the operant training, the concentration of the fecal Hb was significantly higher than that without the operant training (p = 0.009) for ACRN, but there was no significant difference for CRC (p = 0.367). Conclusion: Practical sample collection operant training improves the diagnostic accuracy of the qFIT, which increases the detection of the low concentrations of fecal Hb. Improving the quality of the sample collection could contribute to the diagnostic efficiency of the qFIT in CRC screening.

Probiotic Interventions Alleviate Food Allergy Symptoms Correlated With Cesarean Section: A Murine Model.

Delivery by cesarean section (CS) is linked to an increased incidence of food allergies in children and affects early gut microbiota colonization. Furthermore, emerging evidence has connected disordered intestinal microbiota to food allergies. Here, we investigated the impact of CS on a rat model for food allergy to ovalbumin (OVA). Rats delivered by CS were found to be more responsive to OVA sensitization than vaginally born ones, displaying a greater reduction in rectal temperature upon challenge, worse diarrhea, and higher levels of OVA-specific antibodies and histamine. 16S rRNA sequencing of feces revealed reduced levels of Lactobacillus and Bifidobacterium in the CS rats. Preventative supplementation with a probiotic combination containing Lactobacillus and Bifidobacterium could protect CS rats against an allergic response to OVA, indicating that the microbiota dysbiosis contributes to CS-related response. Additionally, probiotic intervention early in life might help to rebuild aberrant Th2 responses and tight junction proteins, both of which have been linked to CS-related high allergic reactions. Taken together, this study shows that disordered intestinal microbiota plays an essential role in the pathogenesis of food allergy mediated by CS. More importantly, interventions that modulate the microbiota composition in early life are therapeutically relevant for CS-related food allergies.

Complete genome sequencing of Peyer's patches-derived Lactobacillus taiwanensis CLG01, a potential probiotic with antibacterial and immunomodulatory activity.

BACKGROUND: The genus Lactobacillus is an important component of the gastrointestinal tract of human and animals and commonly considered as probiotic. L. taiwanensis has long been proposed to be a probiotic whereas understanding on this species is still in its infancy. Genomic information of L. taiwanensis is fairly limited. Extensive characterization of its beneficial traits is needed. RESULTS: A new strain CLG01 of L. taiwanensis was isolated from mouse Peyer's patches. We established its probiotic profile through in vitro experiments. Complete genome of this strain was also sequenced and analyzed. L. taiwanensis CLG01 showed robust tolerance to acid and a degree of tolerance to bile salt with a promising antibacterial activity against a broad spectrum of pathogenic bacteria. In vitro treatment of mouse RAW 264.7 macrophage cells with heat-killed bacteria and bacterial supernatant of L. taiwanensis CLG01 resulted in enhancement of immune responses and upregulated expression of TNF-α and IL-6. The strain CLG01 also increased the IL-10 production of macrophages when co-treated with lipopolysaccharide (LPS). Complete genome of L. taiwanensis CLG01 contained a 1.89 Mb chromosome and two plasmids. Further genomic analysis revealed the presence of genes related to its resistance to different stresses and the beneficial effects mentioned above. Moreover, biosynthetic gene clusters (BGCs) encoding antimicrobial peptides, like bacteriocin, linear azol(in)e-containing peptide (LAP) and lanthipeptide, were also identified in the genome of L. taiwanensis CLG01. CONCLUSIONS: L. taiwanensis CLG01, isolated from mouse Peyer's patches, is the first L. taiwanensis strain with both phenotypes and genotypes systematically studied. These preliminary data confirmed the role of L. taiwanensis CLG01 as a potential probiotic candidate with antibacterial and immunomodulatory activity, which provide insight for further investigation to this species.

Melatonin Mitigates Oxazolone-Induced Colitis in Microbiota-Dependent Manner.

Levels of type 2 cytokines are elevated in the blood and intestinal tissues of ulcerative colitis (UC) patients in the active phase; this phenomenon indicates the participation of type 2 immune response in UC progression. The beneficial effects of melatonin in dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis models have been illustrated, but its role in the oxazolone (Oxa)-induced colitis model (driven by type 2 immune response) remains relatively unknown. We investigated the relationship between melatonin concentration and the severity of UC, revealing a significantly negative correlation. Subsequently, we investigated the effects of melatonin in Oxa-induced colitis mice and the potential underlying mechanisms. Administration of melatonin significantly counteracted body weight loss, colon shortening, and neutrophil infiltration in Oxa-induced colitis mice. Melatonin treatment mitigated Oxa-induced colitis by suppressing type 2 immune response. In addition, melatonin attenuated intestinal permeability by enhancing the expression of ZO-1 and occludin in colitis mice. Interestingly, the protective effect of melatonin was abolished when the mice were co-housed, indicating that the regulation of gut microbiota by melatonin was critical in alleviating Oxa-induced colitis. Subsequently, 16S rRNA sequencing was performed to explore the microbiota composition. Decreased richness and diversity of intestinal microbiota at the operational taxonomic unit (OTU) level resulted from melatonin treatment. Melatonin also elevated the abundance of Bifidobacterium, a well-known probiotic, and reduced proportions of several harmful bacterial genera, such as Desulfovibrio, Peptococcaceae, and Lachnospiraceae. Fecal microbiota transplantation (FMT) was used to explore the role of microbiota in the function of melatonin in Oxa-induced colitis. Microbiota transplantation from melatonin-treated mice alleviated Oxa-induced colitis, suggesting that the microbiome participates in the relief of Oxa-induced colitis by melatonin. Our findings demonstrate that melatonin ameliorates Oxa-induced colitis in a microbiota-dependent manner, suggesting the therapeutic potential of melatonin in treating type 2 immunity-associated UC.

Real-time artificial intelligence for endoscopic diagnosis of early esophageal squamous cell cancer (with video).

BACKGROUND AND AIMS: Endoscopic diagnosis of early esophageal squamous cell cancer (ESCC) is complicated and dependent on operators' experience. This study aimed to develop an artificial intelligence (AI) model for automatic diagnosis of early ESCC. METHODS: Non-magnifying and magnifying endoscopic images of normal/noncancerous lesions, early ESCC, and advanced esophageal cancer (AEC) were retrospectively obtained from Qilu Hospital of Shandong University. A total of 10,988 images from 5075 cases were chosen for training and validation. Another 2309 images from 1055 cases were collected for testing. One hundred and four real-time videos were also collected to evaluate the diagnostic performance of the AI model. The diagnostic performance of the AI model was compared with endoscopists by magnifying images and the assistant efficiency of the AI model for novices was evaluated. RESULTS: The AI diagnosis for non-magnifying images showed a per-patient accuracy, sensitivity, and specificity of 99.5%, 100%, 99.5% for white light imaging, and 97.0%, 97.2%, 96.4% for optical enhancement/iodine straining images. Regarding diagnosis for magnifying images, the per-patient accuracy, sensitivity, and specificity were 88.1%, 90.9%, and 85.0%. The diagnostic accuracy of the AI model was similar to experts (84.5%, P = 0.205) and superior to novices (68.5%, P = 0.005). The diagnostic performance of novices was significantly improved by AI assistance. When it comes to the diagnosis for real-time videos, the AI model showed acceptable performance as well. CONCLUSIONS: The AI model could accurately recognize early ESCC among noncancerous mucosa and AEC. It could be a potential assistant for endoscopists, especially for novices.

S100A10 Accelerates Aerobic Glycolysis and Malignant Growth by Activating mTOR-Signaling Pathway in Gastric Cancer.

S100 calcium-binding protein A10 (S100A10) is crucially involved in the tumorigenesis of multiple malignant tumors. Reprogrammed glucose metabolism is emerging as a hallmark of various human cancers. However, the function of S100A10 in aerobic glycolysis is unclear. The expression of S100A10 was analyzed using the Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA), The Cancer Genome Atlas (TCGA), and the UALCAN cancer database. Prognostic analysis was performed using the Kaplan-Meier Plotter. The correlation between S100A10 and key glycolytic factors was assessed by GEPIA. The glycolysis level was examined by determining glucose consumption, lactate production, adenosine triphosphate production, cellular oxygen consumption rate, and extracellular acidification rate. Cell apoptosis was investigated by flow cytometry. Colony formation and BrdU assays were performed to detect cell proliferation. A subcutaneous xenograft mouse model was established to evaluate the effects of S100A10 in vivo. Gene Set Enrichment Analysis and western blotting were performed to explore the downstream signaling pathway. S100A10 was significantly upregulated in gastric cancer. Its expression was associated with poor survival. S100A10 increased glucose consumption, lactate production, and the switch from oxidative phosphorylation to aerobic glycolysis. S100A10 promoted malignant proliferation and suppressed cell apoptosis in gastric cancer. S100A10 activated the mTOR pathway by interacting with annexin A2 (ANXA2) to accelerate tumor glycolysis, resulting in tumor malignant progression. S100A10 contributed to aerobic glycolysis and accelerated malignant growth by modulating the Src/ANXA2/AKT/mTOR signaling pathway. Thus, S100A10 may have pivotal roles in gastric cancer.

Acute stress disrupts intestinal homeostasis via GDNF-RET.

OBJECTIVES: Enterochromaffin (EC) cells have been associated with functional gastrointestinal disorders such as IBS. Recently, we found that glial cell-derived neurotrophic factor (GDNF)-rearranged during transfection (RET) localized in EC cells in human colonic epithelia. Here, we examine the role of GDNF-RET in the pathophysiology of diarrhoea-predominant irritable bowel syndrome (IBS-D). MATERIALS AND METHODS: GDNF was assessed by ELISA and immunohistochemistry in biopsies from IBS-D patients and healthy controls. Stress was induced by using a wrap-restraint stress (WRS) procedure to serve as an acute stress-induced IBS model. The function of GDNF-RET axis to intestinal stem cell (ISC) homeostasis, and EC cell numbers were assessed in vivo and in vitro. RESULTS: GDNF-RET was expressed in EC cells in human colon. GDNF was significantly increased in IBS-D patients. WRS mice showed increased GDNF-RET levels in colon. WRS induced visceral hypersensitivity by expanding of ISC and differentiation of EC cell via GDNF-RET. Furthermore, GDNF-treated mice recapitulated the phenotype of WRS mice. In vitro, GDNF treatment amplified Wnt signal and increased serotonin levels in colonic organoids in a dose-dependent manner. CONCLUSIONS: We identified GDNF-RET was presented in colonic epithelium of patients with IBS-D. GDNF-RET played important roles in regulating ISC and EC cell differentiation. Our findings, thus, provide RET inhibitor as new therapeutic targets for treatment of patients with IBS-D.

Endocuff-assisted colonoscopy versus cap-assisted colonoscopy for adenoma detection rate: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Add-on devices have been widely used in clinical practice. The aim of this meta-analysis was to compare the adenoma detection rate between Endocuff-assisted colonoscopy (EAC) and cap-assisted colonoscopy (CAC). METHODS: PubMed, EMBASE, SCOPUS, and Cochrane databases were searched. Outcomes included adenoma detection rate, cecal intubation rate, cecal intubation time, and withdrawal time. Dichotomous data were pooled to obtain the odds ratio or risk ratio. Continuous data were pooled using the mean difference. RESULTS: Of the 240 articles reviewed, six randomized controlled trials were included, with a total of 1994 patients. In the meta-analysis, no statistical difference in adenoma detection rate was detected between EAC and CAC (47.0% vs 45.1%; P = 0.33). EAC significantly improved detection rate of diminutive adenomas/polyps compared with CAC (P = 0.01). Cecal intubation was achieved in 96.5% in EAC group and 97.9% in CAC group (P = 0.04). Besides, no statistical difference was found in cecal intubation time (P = 0.86), withdrawal time (P = 0.88), small adenomas/polyps (P = 0.60), or large adenomas/polyps (P = 0.95). CONCLUSION: EAC and CAC have their respective merits. EAC significantly improve the detection of diminutive adenomas/polyps. CAC was better in cecal intubation rate.

Impact of a real-time automatic quality control system on colorectal polyp and adenoma detection: a prospective randomized controlled study (with videos).

BACKGROUND AND AIMS: Quality control can decrease variations in the performance of colonoscopists and improve the effectiveness of colonoscopy to prevent colorectal cancers. Unfortunately, routine quality control is difficult to carry out because a practical method is lacking. The aim of this study was to develop an automatic quality control system (AQCS) and assess whether it could improve polyp and adenoma detection in clinical practice. METHODS: First, we developed AQCS based on deep convolutional neural network models for timing of the withdrawal phase, supervising withdrawal stability, evaluating bowel preparation, and detecting colorectal polyps. Next, consecutive patients were prospectively randomized to undergo routine colonoscopies with or without the assistance of AQCS. The primary outcome of the study was the adenoma detection rate (ADR) in the AQCS and control groups. RESULTS: A total of 659 patients were enrolled and randomized. A total of 308 and 315 patients were analyzed in the AQCS and control groups, respectively. AQCS significantly increased the ADR (0.289 vs 0.165, P < .001) and the mean number of adenomas per procedure (0.367 vs 0.178, P < .001) compared with the control group. A significant increase was also observed in the polyp detection rate (0.383 vs 0.254, P = .001) and the mean number of polyps detected per procedure (0.575 vs 0.305, P < .001). In addition, the withdrawal time (7.03 minutes vs 5.68 minutes, P < .001) and adequate bowel preparation rate (87.34% vs 80.63%, P = .023) were superior for the AQCS group. CONCLUSIONS: AQCS could effectively improve the performance of colonoscopists during the withdrawal phase and significantly increase polyp and adenoma detection. (Clinical trial registration number: NCT03622281.).

Intranasal oxytocin administration improves depression-like behaviors in adult rats that experienced neonatal maternal deprivation.

Oxytocin (OT), a hypothalamic neuropeptide, has been implicated in the regulation of social behaviors in rodents and humans. This study assessed the effects of intranasal administration of OT on depressive-like behaviors and hippocampal neurogenesis in adult rats following neonatal maternal deprivation (NMD). Here, we show that NMD resulted in significant depression-like behaviors, as indicated by decreases in physical activity and emotional reactivity in a novel environment, in 2-month-old animals. Notably, the OT levels in the plasma, hypothalamus, and hippocampus were decreased in these animals. Intranasal administration of OT reduced the depressive-like behaviors in NMD rats and rescued hippocampal long-term plasticity impaired by NMD stress in rats by promoting hippocampal neurogenesis. These results indicate that OT alleviates the depressive-like behaviors in NMD adult rats, probably mediated by improving adult hippocampal neurogenesis.